tbuckley/cabot-search huggingface dataset:
EXTH-68. SYSTEMIC NEUTRALIZATION OF IL6 SENSITIZES IDH-WILDTYPE GLIOBLASTOMA PRECLINICAL MODELS TO IMMUNE CHECKPOINT INHIBITION
Authors: Jacob Young, Nam Woo Cho, Calixto-Hope Lucas, Kanish Mirchia, Kyounghee Seo, William Chen, Minh Nguyen, Arya Chen, Joanna Phillips, Tomoko Ozawa, Aparna Bhaduri, Manish Aghi, Joseph DeRisi, Mitchel Berger, Nicholas Butowski, Matthew Spitzer, David Raleigh
Journal: Neuro-Oncology (2023)

Abstract IDH-wildtype glioblastomas are resistant to immune checkpoint inhibition (ICI). Here we integrate spatial and single-cell approaches across paired human glioblastomas before or after ICI with functional studies in immunocompetent intracranial mouse glioblastoma models to reveal mechanisms and therapeutic vulnerabilities underlying glioblastoma resistance to ICI. Spatial proteomic and transcriptomic approaches were used to identify biochemical and gene expression programs underlying ICI response or resistance in paired human glioblastoma samples (n = 7). Intracranial SB28 glioblastoma allografts were implanted in C57BL/6J mice and treated with (1) convection enhanced delivery (CED) of AAV9 gene therapy vectors encoding cytokines that reprogram the tumor immune microenvironment (TIME) in other cancers (Il1b, Ccl4, Apoa1), (2) systemic anti-PD1, (3) local anti-IL6, (4) systemic anti-IL6, or (5) combination systemic treatment with anti-PD1 and anti-IL6. Histological, mass cytometry (CyTOF), and multiplexed cytokine assays were used to assess the glioblastoma TIME in response to treatment over time. Mice were monitored for survival and tumor growth was measured using intracranial bioluminescence. Human glioblastomas with radiographic responses to ICI had lower pre-treatment IL6 levels on spatial profiling than glioblastomas resistant to ICI. Intratumor IL6 was suppressed by all AAV9 cytokine conditions compared to AAV9-GFP in mice. Mouse survival was improved by combination systemic treatment with anti-PD1 and anti-IL6, but was not improved by either antibody alone, or by anti-IL6 CED. CyTOF revealed combination systemic therapy reprogrammed the glioblastoma TIME by increasing activated immune cell types such as MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and by decreasing immunosuppressive Tregs. In summary, systemic anti-IL6 in combination with systemic anti-PD1 reprograms the glioblastoma TIME to sensitize preclinical models to ICI. These results provide mechanistic validation of findings from human glioblastomas that respond to ICI and shed light on a therapeutic vulnerability underlying the glioblastoma TIME.
EXTH-80. A SYSTEMIC COMPARISON OF CAR T CELLS, CAR NK CELLS AND CAR MACROPHAGES FOR GLIOMA TREATMENT
Authors: Thomas Look, Serena Fazio, Niklas Binder, Charles L Sentman, Patrick Roth, Cesar Nombela Arrieta, Roman Sankowski, Steve Pascolo, Michael Weller, Tobias Weiss
Journal: Neuro-Oncology (2023)

Abstract Adoptive transfer of engineered immune cells expressing chimeric antigen receptors (CAR) is an emerging cancer immunotherapy that is also being investigated for glioblastoma. Many separate studies focus on either CAR T or CAR NK cells, and CAR macrophages are in early stages of development. However, a systemic cross-comparison of engineered immune effector cells against solid tumors, including glioblastoma, is lacking. Here, we generated second-generation NKG2D CAR mouse and human T cells, NK cells and macrophages and characterized them in vitro in co-culture assays with glioma cells and in vivo in orthotopic glioma mouse models. In vitro, mouse and human CAR T cells and CAR NK cells exhibited the highest tumor-killing activity. In contrast, in vivo, only CAR T cells exhibited anti-tumor activity in two immunocompetent orthotopic glioma-bearing mouse models, whereas CAR NK cells and CAR macrophages failed to prolong survival. More in-depth characterizations using flow cytometry, in vivo imaging and 3D microscopy, revealed that CAR T cells had the best tumor migration properties upon i.v. administration with distinct spatial distribution within the tumor compared to CAR NK cells and CAR macrophages. To profile the effects on bystander immune cells within the tumor microenvironment, we employed flow cytometry and single-cell RNA sequencing. This revealed effector cell-specific effects on the tumor microenvironment and provided insights into why the effective in vitro activity did not translate to in vivo. To unleash the anti-tumor potential of CAR immune effector cells, we engineered them to co-express the pro-inflammatory cytokines IL-12/IFNα2. This improved the in vivo anti-tumor activity of all effector cells and led to the highest fraction of long-term surviving mice with CAR NK cells. This study offers the first cross-comparison of different CAR immune effector cells against gliomas, providing valuable insights for the design of future adoptive cell therapies targeting malignant brain tumors.
CSIG-10. SEX-DIFFERENCES IN NF-ΚB SIGNALING DRIVE SEX-BIASED RESPONSES TOWARDS SENESCENCE AND INFLAMMATION IN GLIOBLASTOMA
Authors: Jason P Wong, Lloyd Tripp, Nicholas Reinhold, Lauren Broestl, Jingqin Luo, Robi D Mitra, Joshua B Rubin
Journal: Neuro-Oncology (2023)

Abstract Male glioblastoma (GBM) patients have a higher incidence rate and worse median survival in comparison to females. The molecular mechanisms that drive these sex differences in incidence and survival are not well understood. Using a murine in vitro GBM model, we identified that male and female cells tend to segregate into two unique groups based on differential gene expression. Male-enriched processes included myc, E2F and G2-M checkpoint signaling. Female-enriched processes included epithelial-mesenchymal transition, interferon responses and TNF-α signaling by NF-κB. Reports from human GBM patients corroborate an increased enrichment for inflammatory and innate immune responses in females. Since the NF-κB pathway regulates senescence and its associated inflammatory response, the senescence-associated secretory phenotype, we examined if there are sex differences in NF-κB signaling as we have reported that female GBM cells undergo senescence more readily. We found that low levels of NF-κB activity were correlated with higher levels of senescence, and that cells from the female-enriched group correspondingly had lower levels of NF-κB activity. Interestingly, p-p65 S536 expression (a marker of increased NF-κB transcriptional activity) was negatively correlated with NF-κB activity in cells within the female-enriched group. Furthermore, female cells with low NF-κB activity responded more readily to TNF-α treatment. These results suggest that female cells can more readily modulate the NF-κB pathway in response to stimuli, thereby poising them towards a pro-inflammatory state. Since inflammation and senescence regulate therapeutic responses in GBM, and we have previously reported that female GBM cells undergo senescence more readily following radiation, these results suggest that further studies to understand the sex differences in NF-κB signaling may improve patient response to radiation and chemotherapy treatment.
DDEL-10. RETROSPECTIVE REVIEW OF INTRA-CSF DRUG DELIVERY: SAFETY AND DRUG DISTRIBUTION PROFILES OF INTRACEREBROVENTRICULAR (ICV), LUMBAR INTRATHECAL (LIT), AND INTRA-CISTERNA MAGNA (ICM) INJECTIONS
Authors: Grace Lee, Marcie Glicksman, Rajan Patel, Nisheka Vanjani, Priya Kumthekar
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The blood-brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics. Given this limitation, intra-cerebrospinal fluid (CSF) drug delivery can be utilized. Here we review and compare thesafety and drug distribution of the different intra-CSF drug delivery methods. METHODS A retrospective literature review of the three most common CSF access methods (intracerebroventricular (ICV), lumbar intrathecal (LIT), and intra-cisterna magna (ICM)) was performed. The search consisted of human clinical trials published on PubMed from 2000 to present, with the following terms: intracerebroventricular/intraventricular/ICV, intrathecal/IT, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF. RESULTS The search yielded 34 ICV, 72 LIT, and 6 ICM studies. To investigate the safety and drug concentration profiles of each delivery method, we excluded studies reporting drug adverse events (AEs) rather than AEs related to the specific drug delivery method, leaving 21 ICV, 30 LIT, and 1 ICM studies, all of which spanned oncology and non-oncology treatment studies. ICV-specific safety was addressed in 10 ICV studies, with infection (N=6) and device malfunction (N=2) being among the most frequently mentioned device/procedure-associated AEs. LIT-specific safety was provided in 17 studies, with post-procedural headache (N=9), infection (N=5), and pain (N=5) being among the most mentioned AEs. For drug distribution, 42.9% (N=9) of ICV studies concluded that ICV delivery achieved sufficient drug exposure in the CNS for a meaningful therapeutic benefit, with drug concentrations reaching minimum effective doses and/or achieving high therapeutic indices. The single ICM study with infusion of bupivacaine for pain management did not analyze safety or drug distribution. Meanwhile, 30.0% (N=9) of LIT studies reached the same conclusion or achieved concentrations consistent with predicted values. CONCLUSION The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild-to-moderate device/procedure-associated AEs. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods.
INNV-02. USAGE TRENDS OF COLLAGEN TILE BRACHYTHERAPY FOR THE FIRST 1000 ORDERS
Authors: Michael Garcia, Adam Turner, Lisa Campbell, David Brachman
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Collagen tile brachytherapy (CTBT) was cleared by the FDA in 2018 for all recurrent intracranial neoplasms and in 2020 for newly diagnosed intracranial neoplasms. We sought to describe usage trends of CTBT by evaluating the first 1000 consecutive orders since CTBT became commercially available in 2019 with respect to tumor type (glioma, brain metastasis, meningioma) and CTBT treatment setting (newly diagnosed, recurrence with prior radiation, recurrence without prior radiation). METHODS Commercial data was accessed using Salesforce, Inc. Coefficient of correlation (r2) was estimated as a measure of orders over time. 1000 orders were divided into 4 time cohorts (Cohort 1 for 1st 250 orders, Cohort 2 for 2nd 250 orders, Cohort 3 for 3rd for 250 orders and Cohort 4 for 4th 250 orders). Order proportions were compared among time cohorts using X2 tests. RESULTS Time period for 1000 orders among 93 centers was 1/23/19–5/11/23. Over these 17 completed yearly quarters there was a positive trend in ordering frequency (r2=0.97). Tumor type was known for 917 orders, of which 52.2% were glioma, 37.4% metastases, and 10.4% meningioma. Proportions of orders for tumor type did not change over time cohorts (p=0.26). Treatment setting was known for 816 orders, of which 80.3% were in recurrence with previous radiation, 14.3% newly diagnosed, and 5.4% recurrence without previous radiation. For glioma and meningioma, treatment setting did not change over time cohorts (p=0.5, p=0.3, respectively). However, for metastases, the proportion of orders for use in the newly diagnosed setting increased over time: 6.4% in Cohort 1, 19.2% in Cohort 2, 21.6% in Cohort 3, 34.7% in Cohort 4 (p&amp;lt; 0.001). CONCLUSION CTBT usage is increasing over time. Proportions of orders among tumor types (glioma, meningioma, metastases) has not changed. However, use of CTBT is increasing in the newly diagnosed setting for brain metastases.
NIMG-85. EVALUATING THE PERFORMANCE OF A DEEP LEARNING GLIOMA SEGMENTATION MODEL USING COMBINED PRE- AND POST-TREATMENT MRI TRAINING DATA
Authors: Sara Ranjbar, Kyle Singleton, Lee Curtin, Lisa Paulson, Kamala Clark-swanson, Andrea Hawkins-daarud, J Ross Mitchell, Pamela Jackson, Kristin Swanson
Journal: Neuro-Oncology (2023)

Abstract Identification of key phenotypic regions such as necrosis, contrast enhancement, and edema on magnetic resonance imaging (MRI) is important for understanding disease evolution and treatment response in patients with glioma. Manual delineation is time intensive and not feasible for a clinical workflow. Automating phenotypic region segmentation overcomes many issues with manual segmentation, however, current glioma segmentation datasets focus on pre-treatment, diagnostic scans, where treat-ment effects and surgical cavities are not present. Thus, existing automatic segmenta-tion models are not applicable to post-treatment imaging that is used for longitudinal evaluation of care. Here, we present a comparison of three-dimensional convolutional neural networks (nnU-Net architecture) trained on large temporally defined pre-treatment, post-treatment, and mixed cohorts. We used a total of 1563 imaging timepoints from 854 patients curated from 13 different institutions as well as diverse public data sets to understand the capabilities and limitations of automatic segmenta-tion on glioma images with different phenotypic and treatment appearance. We as-sessed the performance of models using Dice coefficients on test cases from each group comparing predictions with manual segmentations generated by trained techni-cians. We demonstrate that training a combined model can be as effective as models trained on just one temporal group. The results highlight the importance of a diverse training set, that includes images from the course of disease and with effects from treatment, in the creation of a model that can accurately segment glioma MRIs at multiple treatment time points.
CSIG-13. DIELECTRIC PROPERTIES OF INTRACRANIAL TUMORS – ROLE OF MYELIN CONTENT
Authors: Martin Proescholdt, Amer Haj, Karl-Michael Schebesch, Markus Riemenschneider, Atik Baborie, Nils-Ole Schmidt
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dieclectric properties of brain tumors by analyzing resected tissue. In GBM patients, histological analysis for cellularity, vascularization and myelin content was performed. In addition, sensitivity analyses for specific parameters were conducted. METHODS A cohort of 130 patients with tumors of different histology and malignancy grade have been recruited. Tissue samples were placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz. The measured impedance was translated into dielectric properties (conductivity and relative permittivity) based on the parallel plate model. Myelin, which is the most powerful electric isolator in the brain, was assessed in GBM samples by luxol fast blue staining, and quantified in a three-tier scale. To assess the impact of tissue conditions on the measurements, probes were warmed to 35 degree Celsius, dehydrated or irrigated with 0.9% saline solution. RESULTS We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest and GBM tissue exhibiting the highest conductivity values. GBM samples with very high median conductivity values displayed a consistently lower myelin content. In addition, GBM patients with particularly high conductivity had a significantly shorter overall survival (log rank analysis, p = 0.024). While tissue temperature had no detectable effects on the dielectric properties in GBM, saline irrigation tissue hydration significantly affected the results. CONCLUSION The dielectric properties of intracranial tumors depend on histological class and malignancy grade. GBM patients with high conductivity values showed a significantly poorer prognosis, indicating this parameter as potential marker for TTF efficacy.
BIOM-66. ESTABLISHMENT OF A PROGNOSTIC MODEL FOR GLIOBLASTOMA MULTIFORME MAGNETIC RESONANCE IMAGING BASED ON IMBALANCED CLASSES, CLASSIFICATION, AND KAPLAN-MEIER SURVIVAL CURVE LEARNING ALGORITHMS
Authors: Wen-Yu Cheng, Chih-Chan Yang, JuHsuan Kao, Chiung-Chyi Shen, Yi-Chin Yang, Meng-Yin Yang
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is a rapidly invasive brain tumor with a high mortality rate. It is accompa-nied by peripheral edema. Physicians use magnetic resonance imaging (MRI) to diagnose each patient’s con-dition in clinical practice. The current use of machine learning to classify brain tumors has an accuracy of about 90% in most studies. Therefore, this study aimed to improve its prediction accuracy using machine learning models to predict GBM patient survival or non-survival. The study used MRI T1-related and T2-related sequences to obtain GBM tumor and edema area attributes. It then divided them into four da-tasets: maximum tumor area, maximum edema area, total tumor volume, and total edema volume. These four datasets were used as inputs for classification models based on support vector machines, decision tree algo-rithms, random forest algorithms, and multilayer perceptron (MLP) to predict patient survival. A confusion matrix was used to evaluate each model and determine the most suitable models for each dataset based on their accuracy. MLP was the most appropriate for predicting the overall edema volume dataset, with the highest accuracy in predicting GBM patient survival or non-survival at 96.97%. Hopefully, this study can assist physicians in assessing and diagnosing GBM patients’ survival status in the future. Keywords: Classification Models; Glioblastoma Multiforme; KaplanMeier Curve; Magnetic Resonance Imaging; Peritumoral Edema
EXTH-15. A NOVEL IMMUNE-BASED TREATMENT STRATEGY FOR COMBATTING PROTEIN TUMOR HETEROGENEITY
Authors: Daniel Wilkinson, Ethan Srinivasan, Emily Lerner, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract Cell-based immunotherapy has revolutionized the treatment of many hematological malignancies but has mostly fail against solid tumors, including glioblastoma (GBM). The reason for this failure is multi-fold, but one of the most significant barriers is the extensive intratumoral heterogeneity that characterizes these tumors. Unfortunately, this problem has not been eliminated by personalized medicine strategies aimed at sequencing individual tumors and targeting the uncovered neoantigens. Thinking “outside the box” led us to examine other types of tumor-specific alterations that might more ubiquitously characterize tumor cells, while still being targetable by an immune-based platform. Our investigations led us to the phospholipid phosphatidylserine (PS). PS is typically present on the cytoplasm-facing side of the plasma membrane, where it remains out of view to the immune system. Cellular stresses can lead to dysregulation of processes that keep PS facing internally and instead promote PS exposure on the cell surface. We show here that tumor cells frequently lose the capacity to regulate their plasma membrane and exhibit detectable levels of PS on their surface. Moreover, inducing cell stress through radiation and chemotherapy of tumor cells further enhanced PS exposure. In this study, we aimed to target PS with an immune-based therapy. To this end, we engineered a bi-specific T cell engager (BiTE) consisting of the natural high-affinity PS receptor TIM4 linked to an anti-CD3scFv. This TIM4 BiTE is hypothesized to redirect all T cells to PS, resulting in T cell-mediated killing of tumor cells with exposed PS. Indeed, TIM4 BiTE facilitated potent killing of multiple human tumor cell lines in vitro, including in models of protein heterogeneous tumors. When TIM4 BiTE was delivered intratumorally to a heterogeneous glioma-bearing mouse, survival was significantly extended. These data provide evidence that targeting PS with an immune-based platform represents a potential novel treatment strategy for combatting tumor heterogeneity.
INNV-06. SIGNIFICANCE OF MOLECULAR DIAGNOSTICS FOR THERAPEUTIC DECISION-MAKING IN RECURRENT GLIOMA
Authors: Jens Blobner, Laura Dengler, Sven Blobner, Constantin Eberle, Jonathan Weller, Nico Teske, Philipp Karschnia, Katharina Ruehlmann, Kathrin Heinrich, Frank Ziemann, Philipp Greif, Irmela Jeremias, Rachel Wuerstlein, Korbinian Hasselmann, Mario Dorostkar, Patrick Harter, Stefanie Quach, Veit Stoecklein, Nathalie Albert, Maximilian Niyazi, Joerg-Christian Tonn, Niklas Thon, Benedikt Westphalen, Louisa von Baumgarten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary Molecular Tumor Board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). METHODS We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based upon next-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens and outcome parameters were collected. RESULTS Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32 - 536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), EGFR amplification (19/73; 26%) and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. CONCLUSION In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable anti-tumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.